REM sleep in narcolepsy

Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy

Disorders of Arousal in adults: new diagnostic tools for clinical practice

Abstract Disorders of Arousal (DOA) are mental and motor behaviors arising from NREM sleep. They comprise a spectrum of manifestations of increasing intensity from confusional arousals to sleep terrors to sleepwalking. Although DOA in childhood are usually harmless, in adulthood they are often associated with injurious or violent behaviors to the patient or others. Driving motor vehicles, suspected suicide, and even homicide or attempted homicide have been described during sleepwalking in adults. Furthermore, adult DOA need to be differentiated from other sleep disorders such as Sleep-related Hypermotor Epilepsy or REM Sleep Behavior Disorder. Although many aspects of DOA have been clarified in the last two decades there is still a lack of objective and quantitative diagnostic criteria for DOA. Recent advances in EEG analysis and in the semiological characterization of DOA motor patterns have provided a better definition of DOA diagnosis. Our article focuses on the DOA diagnostic process describing accurately the newest DOA clinical, EEG and video-polysomnographic tools in order to aid clinicians in DOA assessment

Natural history of excessive daytime sleepiness : a population-based 5-year longitudinal study

Study Objective: To document the rates of persistent, remitted, and intermittent excessive daytime sleepiness (EDS) in a longitudinal 5-year community study of adults and to assess how changes in risk factors over time can predict improvement of daytime sleepiness (DS). Methods: Participants were recruited in 2007–2008 as part of a population-based epidemiological study implemented in Canada. They completed postal assessments at baseline and at each yearly follow-up. An Epworth Sleepiness Scale total score >10 indicated clinically significant EDS; a 4-point reduction between two consecutive evaluations defined DS improvement. Socio-demographic, lifestyle, health characteristics, and sleep-related measures (e.g. insomnia symptoms, sleep duration, sleep medication) were self-reported at each time point. Cox proportional-hazard models were used to predict EDS and DS remissions over 5 years. Results: Among the 2167 participants, 33% (n = 714) met criteria for EDS at baseline, of whom 33% had persistent EDS, 44% intermittent EDS, and 23% remitted EDS over the follow-up. Furthermore, 61.4% of 2167 initial participants had stable DS, 27.1% sustained DS improvement and 8.5% transient improvement over the follow-up. The main predictors of EDS remission or DS improvement were normal weight, taking less hypnotics, having hypertension, increased nighttime sleep duration, and decreased insomnia, and depressive symptoms. Conclusion: EDS waxes and wanes over time with frequent periods of remission and is influenced by behavioral characteristics and changes in psychological, metabolic, and nighttime sleep patterns. Targeting these predictors in future interventions is crucial to reduce DS in the general adult population

[18F]Fludeoxyglucose-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia

BackgroundChanges in structural and functional central nervous system have been reported in narcolepsy, with large discrepancies between studies. No study has investigated yet spontaneous brain activity at wake in idiopathic hypersomnia (IH). We compared relative changes in regional brain metabolism in two central hypersomnia conditions with different clinical features, namely narcolepsy type 1 (NT1) and IH, and in healthy controls.MethodsSixteen patients [12 males, median age 30 years (17–78)] with NT1, nine patients [2 males, median age 27 years (20–60)] with IH and 19 healthy controls [16 males, median age 36 years (17–78)] were included. 18F-fludeoxyglucose positron emission tomography (PET) was performed in all drug-free subjects under similar conditions and instructions to stay in a wake resting state.ResultsWe found increased metabolism in the anterior and middle cingulate and the insula in the two pathological conditions as compared to healthy controls. The reverse contrast failed to evidence hypometabolism in patients vs. controls. Comparisons between patient groups were non-significant. At sub-statistical threshold, we found higher right superior occipital gyrus glucose metabolism in narcolepsy and higher middle orbital cortex and supplementary motor area metabolism in IH, findings that require further confirmation.ConclusionThere is significant hypermetabolism in narcolepsy and IH in the wake resting state in a set of brain regions constitutive of the salience cortical network that may reflect a compensatory neurocircuitry activity secondary to sleepiness. Metabolic differences between the two disorders within the executive-control network may be a signature of abnormally functioning neural system leading to persistent drowsiness typical of IH

Executive Control of Attention in Narcolepsy

BACKGROUND: Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness. METHODOLOGY: Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions. PRINCIPAL FINDINGS: Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis. CONCLUSIONS: We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and global intellectual level. Further studies are needed to explore whether medications that promote wakefulness can improve the executive functions in narcolepsy

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment A Randomized Trial

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mgld over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P <0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Peer reviewe

Incidence of narcolepsy after H1N1 influenza and vaccinations : Systematic review and meta-analysis

An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009-2010. The H1N1 vaccine - narcolepsy connection is based on observational studies that are prone to various biases, e.g., confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post-vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix (R)). During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Gut microbiota composition is associated with narcolepsy type 1

Peer reviewe